Hyperargininemia

Hyperargininemia is considered to be the least common urea cycle disorder (UCD) encountered in clinical practice, with estimated incidence rates of 1 in 350,000-1,000,000 [1]. The pathogenesis stems from mutations in genes coding for the catalytic enzyme arginase that is necessary for the conversion of L-arginine to urea and ornithine [2] [3]. Hyperargininemia, like the majority of UCDs, is transferred through an autosomal recessive pattern of inheritance, but the clinical presentation differs from other UCDs in terms of the onset of symptoms and their severity [2] [4]. Namely, patients mainly start to develop first signs after infancy, in the period between ages 2 and 4, while severe hyperammonemia that is typical in other UCDs is often absent [2] [4]. Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones [4] [5]. In the absence of proper therapy, more severe symptoms and signs are noted in a slowly progressive fashion - seizures (generalized tonic-clonic), progressive spastic diplegia, psychomotor and cognitive decline, as well as growth failure [1] [2] [4] [5]. In a subset of cases, episodes of vomiting and lethargy are observed [4]. Furthermore, liver diseases (cholestasis, liver failure, fibrosis, or even hepatocellular carcinoma) can be recognized in some cases of hyperargininemia [3] [6] [7].

Because of the rather rare occurrence of hyperargininemia in clinical practice, the diagnosis might be difficult to attain without adequate clinical suspicion. For this reason, a thorough clinical investigation comprised of a meticulously obtained patient history and a detailed physical examination is of critical importance. The course and progression of symptoms should be assessed with the parents, whereas signs of upper motor neuron damage (hyperreflexia, spasticity) are hallmarks of hyperargininemia on a neurological exam [4]. Furthermore, ataxia, toe walking, and cognitive impairment may be noted [4]. Magnetic resonance imaging (MRI) of the endocranium is a useful procedure in the evaluation of patients suffering from hyperargininemia, showing both cerebral and cerebellar atrophy. Microcephaly could be present in some cases. Electroencephalography (EEG) is also an important component of the diagnostic workup [4], but in order to confirm hyperargininemia, biochemical or genetic testing is necessary. The measured activity of arginase will reveal abnormally low values [4] [5].

1. Maramattom BV, Raja R, Balagopal A. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity. Ann Indian Acad Neurol. 2016;19(3):392-394.
2. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84(3):243-251.
3. Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47(9):1751-1762.
4. Scaglia F, Lee B. Clinical, Biochemical, and Molecular Spectrum of Hyperargininemia Due to Arginase I Deficiency. Am J Med Genet C Semin Med Genet. 2006;0(2):113-120.
5. Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607–610.
6. Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion Tensor Imaging in Arginase Deficiency Reveals Damage to Corticospinal Tracts. Pediatr Neurol. 2010;42(1):49-52.
7. Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap? Mol Genet Metab. 2004;81(Suppl 1):S38–S44.